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A platform trial of neoadjuvant and adjuvant antitumor vaccination alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable pancreatic adenocarcinoma

Heumann, Thatcher; Judkins, Carol; Li, Keyu; Lim, Su Jin; Hoare, Jessica; Parkinson, Rose; Cao, Haihui; Zhang, Tengyi; Gai, Jessica; Celiker, Betul; Zhu, Qingfeng; McPhaul, Thomas; Durham, Jennifer; Purtell, Katrina; Klein, Rachel; Laheru, Daniel; De Jesus-Acosta, Ana; Le, Dung T; Narang, Amol; Anders, Robert; Burkhart, Richard; Burns, William; Soares, Kevin; Wolfgang, Christopher; Thompson, Elizabeth; Jaffee, Elizabeth; Wang, Hao; He, Jin; Zheng, Lei
A neoadjuvant immunotherapy platform clinical trial allows for rapid evaluation of treatment-related changes in tumors and identifying targets to optimize treatment responses. We enrolled patients with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n = 16), with anti-PD-1 antibody nivolumab (Arm B; n = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n = 10), respectively. The primary endpoint for Arms A/B - treatment-related change in IL17A expression in vaccine-induced lymphoid aggregates - was previously published. Here, we report the primary endpoint for Arms B/C: treatment-related change in intratumoral CD8+ CD137+ cells and the secondary outcomes including safety, disease-free and overall survivals for all Arms. Treatment with GVAX+nivolumab+urelumab meets the primary endpoint by significantly increasing intratumoral CD8+ CD137+ cells (p = 0.003) compared to GVAX+Nivolumab. All treatments are well-tolerated. Median disease-free and overall survivals, respectively, are 13.90/14.98/33.51 and 23.59/27.01/35.55 months for Arms A/B/C. GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p = 0.242; HR = 0.51, p = 0.173) and overall survival (HR = 0.59, p = 0.377; HR = 0.53, p = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study.
PMCID:10281953
PMID: 37339979
ISSN: 2041-1723
CID: 5538452

Challenges of the current precision medicine approach for pancreatic cancer: A single institution experience between 2013 and 2017

Ding, Ding; Javed, Ammar A; Cunningham, Dea; Teinor, Jonathan; Wright, Michael; Javed, Zunaira N; Wilt, Cara; Parish, Lindsay; Hodgin, Mary; Ryan, Amy; Judkins, Carol; McIntyre, Keith; Klein, Rachel; Azad, Nilo; Lee, Valerie; Donehower, Ross; De Jesus-Acosta, Ana; Murphy, Adrian; Le, Dung T; Shin, Eun Ji; Lennon, Anne Marie; Khashab, Mouen; Singh, Vikesh; Klein, Alison P; Roberts, Nicholas J; Hacker-Prietz, Amy; Manos, Lindsey; Walsh, Christi; Groshek, Lara; Brown, Caitlin; Yuan, Chunhui; Blair, Alex B; Groot, Vincent; Gemenetzis, Georgios; Yu, Jun; Weiss, Matthew J; Burkhart, Richard A; Burns, William R; He, Jin; Cameron, John L; Narang, Amol; Zaheer, Atif; Fishman, Elliot K; Thompson, Elizabeth D; Anders, Robert; Hruban, Ralph H; Jaffee, Elizabeth; Wolfgang, Christopher L; Zheng, Lei; Laheru, Daniel A
Recent research on genomic profiling of pancreatic ductal adenocarcinoma (PDAC) has identified many potentially actionable alterations. However, the feasibility of using genomic profiling to guide routine clinical decision making for PDAC patients remains unclear. We retrospectively reviewed PDAC patients between October 2013 and December 2017, who underwent treatment at the Johns Hopkins Hospital and had clinical tumor next-generation sequencing (NGS) through commercial resources. Ninety-two patients with 93 tumors tested were included. Forty-eight (52%) patients had potentially curative surgeries. The median time from the tissue available to the NGS testing ordered was 229 days (interquartile range 62-415). A total of three (3%) patients had matched targeted therapies based on genomic profiling results. Genomic profiling guided personalized treatment for PDAC patients is feasible, but the percentage of patients who receive targeted therapy is low. The main challenges are ordering NGS testing early in the clinical course of the disease and the limited evidence of using a targeted approach in these patients. A real-time department level genomic testing ordering system in combination with an evidence-based flagging system for potentially actionable alterations could help address these shortcomings.
PMID: 33127389
ISSN: 1872-7980
CID: 4741732

Correlates of nicotine dependence in men with childhood attention-deficit/hyperactivity disorder: a 33-year follow-up

Garcia Murillo, Lourdes; Ramos-Olazagasti, Maria A; Klein, Rachel G; Mannuzza, Salvatore; Castellanos, Francisco Xavier
Identify correlates of nicotine dependence [lifetime (l) and ongoing (o)] in adults with attention-deficit/hyperactivity disorder (ADHD) in childhood. We conducted a 33-year prospective follow-up of boys (mean age 8) with combined type ADHD (n = 135/207, 65% original sample). Correlates of nicotine dependence in adulthood were selected from characteristics obtained in childhood and adolescence. Among selected childhood features, only immature behavior was significantly related to nicotine dependence (OR(o) = 0.29, p = 0.02), indexing decreased risk. In contrast, several adolescent variables significantly correlated (p < 0.01) with nicotine dependence at mean age 41, including alcohol substance use disorder (SUD, OR(l) = 4.97), non-alcohol SUD (OR(o) = 4.33/OR(l) = 10.93), parental antisocial personality disorder (OR(l) = 4.42), parental SUD (OR(l) = 3.58), dropped out of school (OR(l) = 2.29), impulsivity (OR(o) = 1.53/OR(l) = 1.59), hyperactivity (OR(o) = 1.38), and number of antisocial behaviors (OR(o) = 1.10/OR(l) = 1.14). Results highlight the role of adolescent psychopathology in the development of nicotine dependence, motivating prospective longitudinal efforts to better define the developmental trajectories of risk and protection.
PMID: 30171588
ISSN: 1866-6647
CID: 3273872

Predicting the Adult Functional Outcomes of Boys With ADHD 33 Years Later

Ramos-Olazagasti, María A; Castellanos, Francisco Xavier; Mannuzza, Salvatore; Klein, Rachel G
OBJECTIVE:Little is known of the factors that influence the course of childhood attention-deficit/hyperactivity disorder (ADHD). Objectives were to identify early features predictive of the adult outcome of children with ADHD. In the longest prospective follow-up to date of children with ADHD, predictors of multiple functional domains were examined: social, occupational, and overall adjustment and educational and occupational attainment. METHOD/METHODS:White boys (6-12 years, mean age 8 years) with ADHD (N = 135), selected to be free of conduct disorder, were assessed longitudinally through adulthood (mean age 41) by clinicians blinded to all previous characteristics. Predictors had been recorded in childhood and adolescence (mean age 18). RESULTS:Childhood IQ was positively associated with several outcomes: educational attainment, occupational rank, and social and occupational adjustment. Despite their low severity, conduct problems in childhood were negatively related to overall function, educational attainment, and occupational functioning. Two other childhood features that had positive associations with adult adjustment were socioeconomic status and reading ability, which predicted educational attainment. Of multiple adolescent characteristics, 4 were significant predictors: antisocial behaviors predicted poorer educational attainment; educational goals were related to better overall function; early job functioning had a positive relation with social functioning; and early social functioning was positively related to occupational functioning. CONCLUSION/CONCLUSIONS:Other than childhood IQ, which predicted better outcomes in several domains, there were no consistent prognosticators of adult function among children with ADHD. Providing additional supports to children with relatively lower IQ might improve the adult functional outcome of children with ADHD. However, predicting the course of children with ADHD remains a challenge.
PMCID:6126351
PMID: 30071978
ISSN: 1527-5418
CID: 3217182

A Double-Blind Placebo-Controlled Trial of Omega-3 Fatty Acids as a Monotherapy for Adolescent Depression

Gabbay, Vilma; Freed, Rachel D; Alonso, Carmen M; Senger, Stefanie; Stadterman, Jill; Davison, Beth A; Klein, Rachel G
OBJECTIVE:Reports are mixed on the efficacy of omega-3 fatty acids (O3FA) for the treatment of major depressive disorder (MDD), with only limited data in adolescents. The present trial aimed to investigate systematically the efficacy of O3FA as a monotherapy, compared to a placebo, in adolescents with MDD. Secondarily, we explored O3FA effects on anhedonia, irritability, and suicidality-all key features of adolescent MDD. METHODS:Fifty-one psychotropic medication-free adolescents with DSM-IV-TR diagnoses of MDD (aged 12-19 years; 57% female) were randomized to receive O3FA or a placebo for 10 weeks. Data were collected between January 2006 and June 2013. O3FA and a placebo were administered on a fixed-flexible dose titration schedule based on clinical response and side effects. The initial dose of 1.2 g/d was increased 0.6 g/d every 2 weeks, up to a maximum of 3.6 g/d. Clinician-rated and self-rated depression severity, along with treatment response, served as primary outcome measures. Additionally, we examined O3FA effects on depression-related symptoms, including anhedonia, irritability, and suicidality. Treatment differences were analyzed via intent-to-treat analyses. RESULTS:O3FA were not superior to a placebo on any clinical feature, including depression severity and levels of anhedonia, irritability, or suicidality. Additionally, response rates were comparable between treatment groups. Within-treatment analyses indicated that both treatments were associated with significant improvement in depression severity on self- (O3FA: t = -4.38, P < .001; placebo: t = -3.52, P = .002) and clinician (O3FA: t = -6.47, P < .001; placebo: t = -8.10, P < .001) ratings. CONCLUSIONS:In adolescents with MDD, O3FA do not appear to be superior to placebo. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov identifier: NCT00962598.
PMID: 29985566
ISSN: 1555-2101
CID: 3192232

Altered intrinsic functional connectivity of the cingulate cortex in children with severe temper outbursts

Roy, Amy Krain; Bennett, Randi; Posner, Jonathan; Hulvershorn, Leslie; Castellanos, F Xavier; Klein, Rachel G
Severe temper outbursts (STO) in children are associated with impaired school and family functioning and may contribute to negative outcomes. These outbursts can be conceptualized as excessive frustration responses reflecting reduced emotion regulation capacity. The anterior cingulate cortex (ACC) has been implicated in negative affect as well as emotional control, and exhibits disrupted function in children with elevated irritability and outbursts. This study examined the intrinsic functional connectivity (iFC) of a region of the ACC, the anterior midcingulate cortex (aMCC), in 5- to 9-year-old children with STO (n = 20), comparing them to children with attention-deficit/hyperactivity disorder (ADHD) without outbursts (ADHD; n = 18). Additional analyses compared results to a sample of healthy children (HC; n = 18) and examined specific associations with behavioral and emotional dysregulation. Compared to the ADHD group, STO children exhibited reduced iFC between the aMCC and surrounding regions of the ACC, and increased iFC between the aMCC and precuneus. These differences were also seen between the STO and HC groups; ADHD and HC groups did not differ. Specificity analyses found associations between aMCC-ACC connectivity and hyperactivity, and between aMCC-precuneus iFC and emotion dysregulation. Disruption in aMCC networks may underlie the behavioral and emotional dysregulation characteristic of children with STO.
PMCID:5812860
PMID: 28803557
ISSN: 1469-2198
CID: 2670892

Severe temper outbursts as indicators of irritability in young children [Meeting Abstract]

Roy, A K; De, Serisy M; Bennett, R; Castellanos, F X; Klein, R G
Objectives: Temper outbursts are frequently considered symptoms of irritability within the context of ODD, mood disorder, and anxiety disorder. However, even when chronic irritability is not present, they are associated with significant functional impairments. We will provide an overview of our research program that takes a multimodal approach to understanding severe temper outbursts in young children. Methods: We evaluated 216 boys and girls (ages 5-9 years; 73% boys) from diverse socioeconomic backgrounds who comprised three groups: 1) children with severe temper outbursts (STO; n = 80); 2) children with ADHD without outbursts (ADHD; n = 79); and 3) typically developing children (TDC; n = 57). Severe temper outbursts were defined as follows: 1) occurring at least three times per week; 2) lasting >10 minutes; 3) excessive for developmental level; and 4) causing significant impairment. Parents completed a semistructured diagnostic interview about their child and questionnaires about their child's behavior and emotion regulation skills. Children completed brief IQ and language screeners, questionnaires about their emotions and behavior, and tasks assessing frustration tolerance and emotion regulation. A number of these children (64 percent) successfully completed an MRI session that included resting-state, structural, and diffusion tension imaging scans. Results: Approximately 84 percent of the STO group received an ADHD diagnosis, 67 percent were diagnosed with ODD, 28 percent were diagnosed with an anxiety disorder, and 12 percent were diagnosed with a mood disorder. Few exhibited chronic irritabilities based on parent report. On an emotion regulation task, the STO group demonstrated deficits in regulating negative affect in response to frustration. Findings from the resting-state fMRI analyses suggest disruptions in dorsal anterior cingulate cortex (dACC) circuitry associated with tantrum severity. Tantrum severity was also related to cortical thickness of the dACC. Conclusions: Children with severe temper outbursts represent a highly impaired group, even when chronic irritability is not present. Evidence suggests an association between these outbursts and disruptions in dACC circuitry, a region implicated in the expression and regulation of frustration. Such findings have important implications for future conceptualization and treatment of young children with severe temper outbursts
EMBASE:620081072
ISSN: 1527-5418
CID: 2924182

Long-term outcomes of childhood attention deficit hyperactivity disorder: The New York study

Chapter by: Houssais, Sylviane; Hechtman, Lily; Klein, Rachel G
in: Attention deficit hyperactivity disorder: Adult outcome and its predictors by Hechtman, Lily [Eds]
New York, NY, US: Oxford University Press, 2017
pp. 31-62
ISBN: 978-0-19-021358-9
CID: 2523242

The Association of Youth and Caregiver Anxiety and Asthma Care among Urban Young Adolescents

Bruzzese, Jean-Marie; Reigada, Laura C; Lamm, Alexandra; Wang, Jing; Li, Meng; Zandieh, Stephanie O; Klein, Rachel G
OBJECTIVE: To examine the association of adolescent asthma-related anxiety, social anxiety, separation anxiety, and caregiver asthma-related anxiety, with asthma care by urban adolescents. METHODS: Participants were 386 ethnic minority adolescents (mean age=12.8) with persistent asthma and their caregivers. Adolescents reported what they do to prevent asthma symptoms and to manage acute symptoms, and if they or their caregiver is responsible for their asthma care. Adolescents completed the Youth Asthma-related Anxiety Scale, and the social and separation anxiety subscales of the SCARED; caregivers completed the Parent Asthma-related Anxiety Scale. Linearity of the associations was assessed via Generalized Additive Models (GAM). When there was no evidence for non-linearity, linear mixed effects models were employed to evaluate the effects of the predictors. RESULTS: Adolescents asthma-related anxiety had a strong curvilinear relationship with symptom prevention (P<0.001). Adolescents took more prevention steps as their anxiety increased, with a plateau at moderate anxiety. There was a linear relationship of adolescent asthma-related anxiety to symptom management (beta=0.03, P=.021) and to asthma responsibility (beta=0.11, P=.015), and of caregiver asthma-related anxiety to adolescent symptom prevention (beta=0.04, P=.001). Adolescent social and separation anxiety had weak-to-no relationship with asthma care. Results remained consistent when controlling for each of the other anxieties. CONCLUSIONS: Asthma-related anxiety plays an important, independent role in asthma care. When low, adolescents may benefit from increased support from caregivers and awareness of the consequences of uncontrolled asthma. When elevated, health providers should ensure the adolescents are not assuming responsibility for asthma care prematurely.
PMCID:5047850
PMID: 27049680
ISSN: 1876-2867
CID: 2066122

Can school counselors deliver cognitive-behavioral treatment for social anxiety effectively? A randomized controlled trial

Masia Warner, Carrie; Colognori, Daniela; Brice, Chad; Herzig, Kathleen; Mufson, Laura; Lynch, Chelsea; Reiss, Philip T; Petkova, Eva; Fox, Jeremy; Moceri, Dominic C; Ryan, Julie; Klein, Rachel G
BACKGROUND: Social anxiety disorder (SAD) typically onsets in adolescence and is associated with multiple impairments. Despite promising clinical interventions, most socially anxious adolescents remain untreated. To address this clinical neglect, we developed a school-based, 12-week group intervention for youth with SAD, Skills for Academic and Social Success (SASS). When implemented by psychologists, SASS has been found effective. To promote dissemination and optimize treatment access, we tested whether school counselors could be effective treatment providers. METHOD: We randomized 138, ninth through 11th graders with SAD to one of three conditions: (a) SASS delivered by school counselors (C-SASS), (b) SASS delivered by psychologists (P-SASS), or (c) a control condition, Skills for Life (SFL), a nonspecific counseling program. Blind, independent, evaluations were conducted with parents and adolescents at baseline, post-intervention, and 5 months beyond treatment completion. We hypothesized that C-SASS and P-SASS would be superior to the control, immediately after treatment and at follow-up. No prediction was made about the relative efficacy of C-SASS and P-SASS. RESULTS: Compared to controls, adolescents treated with C-SASS or P-SASS experienced significantly greater improvement and reductions of anxiety at the end of treatment and follow-up. There were no significant differences between SASS delivered by school counselors and psychologists. CONCLUSION: With training, school counselors are effective treatment providers to adolescents with social anxiety, yielding benefits comparable to those obtained by specialized psychologists. Questions remain regarding means to maintain counselors' practice standards without external support.
PMID: 27002215
ISSN: 1469-7610
CID: 2052022